tbuckley/cabot-search huggingface dataset:
Examination of mutation signature and mutation spectrum as predictors of response to immune checkpoint blockade therapy.
Authors: Danae Bowen, Stephen Capone, Gino Kim In, Rémi Buisson
Journal: Journal of Clinical Oncology (2022)

2537 Background: In recent years, there has been promising progress in the use of immune checkpoint blockade (ICB) as a treatment for various cancer types such as lung, kidney, bladder, skin, colon, and breast cancer. In order for this modality to have increased success, more precise selection tools are needed to predict which patients will benefit from treatment. Tumor Mutational burden (TMB) has been implicated as a biomarker for ICB response due to the increased tumor immunogenicity present in high TMB samples. However, we hypothesize that the quality of mutations may also have an impact in determining immune response, rather than just the quantity of mutations alone. Methods: A retrospective analysis of 2041 patients across multiple solid tumor types was conducted using an open-access, open-source cancer genomics database (Gao, Sci Signal, 2013), with the goal of assessing the influence of mutational signature on patient response to ICB (including CTLA-4, PD-1, and PDL-1). Patient demographics, treatment variables/outcomes, and tumor variables, including mutation spectrum, and mutation count, were evaluated. A paired two sample test for means was used to analyze data with p &lt; 0.05 considered statistically significant. Response outcomes were determined per RECIST v 1.1. Results: Our data demonstrate that mutational spectrum profiles show distinct patterns when considering response to ICB, independent of TMB. Patients with breast invasive ductal carcinoma who responded to ICB had less C &gt; A mutations ( p = 0.020) and more C &gt; T mutations ( p = 0.017) compared to non-responders. Lung adenocarcinoma responders had less C &gt; T mutations ( p = 0.003) and more C &gt; A mutations ( p = 0.0003) compared to non-responders. Furthermore, both head and neck squamous cell carcinoma and glioblastoma multiforme responders had more T &gt; A mutations ( p = 0.047 and p = 0.011, respectively) than non-responders. However, in other cancer types studied (urothelial, colon, renal, lung squamous, and melanoma), there were no obvious trends to distinguish responders from non-responders. Preferentially mutated gene targets were also considered for all 10 cancer types (including CARD11, SMARCA4, GLI1, PIK3R1, PTPRT, among others), many of which were also tied to the unique mutational signatures observed and which may be separately identified as novel ICB therapy targets. Conclusions: We found that specific mutation type may impact response to ICB in at least 4 cancer types, including breast, lung adenocarcinoma, head and neck squamous cell carcinoma and glioblastoma multiforme. Of note, this trend was not found in other cancer types which are typically found to have higher TMB. Moving away from solely considering the magnitude of mutations in tumor samples and towards identifying specific mutational signatures may aid in providing necessary specificity for selecting patients for ICB cancer therapy.
Impact of turnaround time (TAT) of molecular testing on initial treatment (Tx) in newly diagnosed stage 4 non-small cell lung cancer (NSCLC 4): An Integra Connect (IC) retrospective observational study.
Authors: Mike Gart, Lucio N. Gordan, Rushir J. Choksi, Daniel P. Petro, Jeffrey A. Scott, Prateesh Varughese, Erin Alwon, Robert E. Smith
Journal: Journal of Clinical Oncology (2022)

e13510 Background: Broad molecular profile-based initiation of Tx in newly diagnosed NSCLC 4 (KF Mileham, Cancer Med, 2022) is advocated by NCCN guidelines. Despite this, Tx is often started prior to, and without knowledge of, an actionable oncogenic driver (AOD), and often without subsequent switch to appropriate tyrosine kinase inhibitor (TKI). In this study we sought to assess the impact of TAT of genomic testing on Tx in patients harboring a potentially actionable EGFR mutation. Methods: By interrogating the IC curated database, we identified 2,357 newly diagnosed NSCLC 4 patients (pts) who started an initial line of therapy (LOT 1) between 1/1/2019 and 12/31/2021. Squamous carcinoma pts were excluded unless documented to be never smokers or &lt;age 40. We assessed testing across all sample types and performed the analysis on solid tumor tissue next-generation sequence (NGS) tested patients. We used an order for EGFR as a surrogate for AOD evaluation and collected date of order and reporting of EGFR test results, and date of 1 st Tx start. From this, we calculated TAT and whether Tx was initiated after genomic results. In addition, we captured whether testing was in-house or by reference lab (RL). We looked at the RLs that comprise of the top 85% of NGS test sources, where the testing source was known. We removed records where test order dates and results dates were the same date, where test order dates or results dates were unknown, and where TAT &gt; 90 days. EGFR Effective Testing Rate (EETR) is defined as EGFR result prior to line 1 Tx start. Results: Median age was 70 (range 40 - 89) and 50% male. Pts with TAT of ≤7 days had an 82% EETR vs. Pts with TAT of &gt;29 days had a 61% EETR. Overall, RLs had a median TAT of 19 days with a 72% EETR, whereas in-house labs had a median TAT of 15 days with a EETR of 80%. Conclusions: When providers and patients can obtain test results within 21 days of test order there is a higher likelihood of waiting for the test result to start Tx. Many community oncology practices are contemplating implementing in-house testing solutions to improve rates of testing and turnaround time of testing. This may prove to be an effective strategy given the better TAT for in-house testing. When there is faster TAT, patients and providers wait to start initial Tx. Getting patients on appropriate therapy based on their biomarker status can improve overall survival.[Table: see text]
Analytical validation of OriMIRACLE S, a personalized and tumor-informed approach to minimal residual disease surveillance.
Authors: Zhendong Li, Weirong Zhao, Yanhui Gan, Xin Zheng, Jicheng Yao, Feng Li, Weifeng Wang
Journal: Journal of Clinical Oncology (2022)

e15013 Background: The presence of minimal residual disease (MRD) after curative-intent therapies in solid tumors is recognized as a risk factor for relapse. Glycoprotein-based tumor markers lack sensitivity and specificity for clinical application. Circulating tumor DNA (ctDNA) based MRD detection which can identify disease relapse ahead of radiological imaging has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection via plasma cell-free DNA. Methods: Tumor-specific somatic single nucleotide variants (SNVs) were identified by whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected by OriSelector algorithm for patient-specific multiplex PCR-based NGS assay for MRD tracking. The limit of detection (LOD), specificity, sensitivity, repeatability, and reproducibility of this assay were determined experimentally with a series of standard references and in silico. Standard references were developed as following for assessing assay performance. The somatic variant references were two commercialized standards each containing five positive sites at variant allele frequency [VAF] of 0.1% and 1%, and a wild type sample. The single nucleotide polymorphism (SNP) references were made by blending three gDNA samples (160 sites) with gDNA samples without these SNPs to VAFs of 0%, 0.005%, 0.01%, 0.02%, 0.05% and 0.1%. And cfDNA references were made by titrating the clinical cfDNA mixture from five patients containing 31 positive sites with mononucleosomal HEK293 DNA to VAFs of 0.01-0.3% and 0.1-3%. Results: Site level sensitivity of ctDNA samples were 68.8% to 100% with 10 to 50ng input ctDNA (3,000 to 15,000 haploid genome equivalents). Site level reproducibility and repeatability were 98.0% and 97.0% using somatic variant references, respectively. The detection of three positive sites was sufficient to achieve a nearly 100% overall sample level sensitivity and specificity (6,000 haploid genome equivalents of gDNA samples) determined either by calculating a binomial probability or in silico with customized panels have 21 to 30 variants. The LOD of this assay was as low as 0.01% with the algorithm of OriCleverClover which could filter process and sequencing-related artifacts. Conclusions: OriMIRACLE S has been analytically validated as a highly sensitive and specific method to detect low quantities of ctDNA in plasma. The low limit of detection at a VAF of only 0.01% with low DNA input. OriMIRACLE S has wide-ranging potential applications in the clinical setting and drug development in a real-world scenario.
Tumour ERO1A instigates T cell dysfunction by transmission of endoplasmic reticulum stress.
Authors: Lihui Liu, Sini Li, Yan Qu, Jian Wang, Kailun Fei, Chao Wang, Xue Zhang, Zixiao Ma, Hua Bai, Jie Wang
Journal: Journal of Clinical Oncology (2022)

e14533 Background: Infiltrated-excluded tumor microenvironment (TME) predicts poor prognoses in multiple malignancies. T cell dysfunction is a hallmark of immune exclusion in patients and correlates with response to immune checkpoint inhibitors (ICIs). However, strategies to classify TME based on T cell dysfunction for predicting response to ICIs are lacking. Methods: MC-38, LLC, and 4T1 tumours knocked out and restored for endoplasmic reticulum oxidoreductin-1α ( Ero1a) were engrafted subcutaneously into immunocompetent hosts. Anti-PD-1 antibody was injected intraperitoneally every three days. We used immunofluorescence staining and flow cytometry to characterize the intratumoral infiltrates. Coculturing of tumour cells with T cells, single-cell RNA-seq, and western blotting were utilized to unveil the underlying mechanisms. Multi-color immunohistochemistry was used to identify the expression of ERO1A and define TME in patient samples. Results: Here, we show that ERO1A, an oxidoreductase involved in endoplasmic reticulum stress (ER stress)-induced apoptosis, instigates an immune-exclusive TME by transmitting ER stress to T cells. In mouse models, knocking out of Ero1a in Ero1a-expressed tumours promotes the infiltration of CD8 + T cells and enhances responses to anti-PD-1 treatment. By contrast, ectopic expression of Ero1a enhances tolerance to ER stress in tumour cells by activating IRE1α-signaling. Additionally, ero1a promotes the transmission of ER stress to T cells and triggers CHOP-dependent apoptosis, resulting in an immune-exclusive TME. Elimination of ER stress status suppresses tumour growth in immunocompetent mice and promotes response to ICIs. In 37 patients with non-small cell lung cancer treated with neoadjuvant immunotherapy, the expression of ERO1A is negatively correlated with the abundance of tumour infiltrated lymphocytes ( P&lt; 0.001) and responses to ICIs ( P&lt; 0.001). Patients with low expression of ERO1A also exhibit a superior recurrence-free survival compared to those with high expression of ERO1A ( P= 0.039). Conclusions: Together, our findings identify a mechanism for immune-exclusive TME and suggest a potential immunotherapeutic target for terminating T cell dysfunction and apoptosis through eliminating transmissible ER stress.[Table: see text]
ZENYTH-ESO: Master protocol to assess the safety and recommended phase II dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and myxoid/round cell liposarcoma [Substudy 3, GSK4427296].
Authors: Dejka M. Araujo, Brian H. Ladle, Kai He, Benjamin Powers, Amanda McGillivray, Ionel Mitrica, Wenlei Liu, Nitin Patel, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2022)

TPS2681 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing an affinity-enhanced T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapy, GSK4427296, utilizes the same TCR as lete-cel, as well as an epigenetic reprogramming process (Epi-R) developed by Lyell Immunopharma to alter the phenotypic T-cell profile of the manufactured product, and is intended to increase the proportion of cells with properties of durable stemness. T cells with properties of durable stemness are able to proliferate, persist, and self-renew with anti-tumor functionality. A first-time-in-human master protocol (NCT04526509) is underway to evaluate the safety, tolerability, and recommended phase II dose (RP2D) of next generation NY-ESO-1 TCR T-cell therapies. Substudy 3 is added to this master protocol to assess GSK4427296 in patients with advanced synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS). Methods: This substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage, aiming to dose 10 participants at the RP2D. Key inclusion criteria: age ≥18 years; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation or MRCLS with a translocation involving DDIT3 and/or FUS and/or EWSR1 genes; and anthracycline-based therapy receipt/completion/intolerance. Key exclusion criteria: prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene or allogenic stem cell/solid organ transplant; and central nervous system metastases. Primary endpoints: safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints: investigator-assessed overall response rate, duration of response, maximum transgene expansion (C max ), T max , and AUC (0-t) . Analyses will be descriptive. The master protocol is open for recruitment. Clinical trial information: NCT04526509.
Outcomes of recurrent and metastatic endometrial cancer (RMEC) treated with systemic progestins.
Authors: Anjali Kulkarni, Natalie Andrews Wright, Alyssa N Forget, Ranjeeta Mallick, Tim O Ramsay, Johanne I Weberpals
Journal: Journal of Clinical Oncology (2022)

5585 Background: Recurrent endometrial cancer has a poor prognosis with limited treatment options. Systemic therapy for RMEC includes chemotherapy, immunotherapy and hormonal therapy. Although studies on hormonal therapy have described modest results, agents such as megestrol acetate (megace) continue to be used mainly for low grade, ER+/PR+ve tumors in the advanced and recurrent setting. Overall response rates have been reported in the range of 20-25% with responses up to 25-35% in ER+/PR+ve tumors. Despite comparative response rates to chemotherapy, the use of hormonal therapy in clinical trials in RMEC is hampered by a lack of clear progression-free survival (PFS) data. The primary objective of this study is to determine the PFS in RMEC patients treated with progestins. Methods: A retrospective chart review on RMEC was conducted at The Ottawa Hospital with data sourced from medical records. Main inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥1 one line of progestin treatment. PFS was the time from initiation of progestin therapy until progression of disease (PD) by imaging, biopsy or death. Overall survival (OS) was the time from initiation of progestins until death. Median time to PFS and OS were estimated using the Kaplan-Meier method and compared using a Log-rank Test with 95% confidence interval (CI). Results: Of 2342 cases reviewed, 75 met inclusion criteria. The mean age at the time of primary diagnosis was 66.7 years and the range of follow-up was 1-199 months (mo). Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of all patients by grade was: 1: 25 (33.3%), 2: 30 (40.0%) and 3: 20 (26.7%). The median PFS for all patients with grade 1 and 2 RMEC was 15.7 mo (95% CI: 8.0, 19.5), compared to 5.0 mo (3.0, 23.0) for grade 3 disease (p=0.28). The median OS for all patients with grade 1 and 2 versus grade 3 RMEC, was 25.9 mo (15.3, 40.3) versus 12.5 mo (5.7, 35.9), respectively (p=0.12). The number of patients treated with 0 and ≥1 line of chemotherapy was 34 (45.3%) and 41 (54.7%). The median PFS for patients who were naïve to chemotherapy was 17.9 mo (14.3, 27.0), compared to 6.2 mo (3.9, 14.8) for patients who had received ≥1 prior lines of treatment (p=0.09). The median OS was 29.1 mo (17.9, 61.1) for patients who were naïve to chemotherapy, versus 23.0 mo (10.5, 37.6) for patients who were previously exposed (p=0.64). Conclusions: This real-world data suggests that progestins for RMEC have comparable outcomes to other systemic therapies in chemotherapy-exposed patients. Progestins such as megestrol acetate may be considered in the design of RMEC clinical trials.
CSF proteomics for differentiation of brain malignancies.
Authors: Nicholas Mikolajewicz, Mara Trifoi, Shahbaz Khan, Michael J. Glantz, Jason Moffat, Gelareh Zadeh, Thomas Kislinger, Alireza Mansouri
Journal: Journal of Clinical Oncology (2022)

2021 Background: Accurate diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Although the cerebrospinal fluid (CSF) is the ideal liquid biopsy source, the traditionally high volumes required for impactful analyses have deterred progress. The objective of this study was to identify diagnostic and prognostic CSF proteomic signatures in glioblastoma (GBM), brain metastases (BM), and central nervous system lymphoma (CNSL). Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics with ultra-low sample volumes. Proteomic signatures were identified using machine learning classifiers and survival analyses. Results: Using 30µL CSF volumes, we recovered 800 unique peptides across 73 samples [20 normal pressure hydrocephalus (NPH, non-tumor control), 22 GBM, 17 BM, and 14 CNSL]. Externally-validated proteomic-based classifiers identified malignancy with AUROC of 0.94 and distinguished individual tumor entities from others with AUROC ≥0.96. More clinically relevant triplex classifiers, comprised of just 3 peptides, distinguished individual tumor entities with AUROC ≥0.90. Novel biomarkers were identified among the top classifiers, including TFF3 and CACNA2D2, and characterized using single-cell RNA sequencing data. Survival analyses validated previously implicated prognostic signatures, including blood brain barrier disruption. Conclusions: Reliable classification of intra-axial malignancies using ultra-low CSF volumes is feasible, which has ramifications for longitudinal tumor surveillance. Novel biomarkers identified here necessitate future validation. Based on emerging evidence, upfront implantation of CSF reservoirs in brain tumor patients warrants consideration.
Association of DNA damage response (DDR) gene mutations (mts) and response to neoadjuvant cisplatin-based chemotherapy (chemo) in muscle-invasive bladder cancer (MIBC) patients (pts) enrolled onto SWOG S1314.
Authors: Gopa Iyer, Catherine Tangen, Michal Sarfaty, Ashley Marie Regazzi, I-Ling C. Lee, Woonyoung Choi, Colin P.N. Dinney, Thomas W. Flaig, Ian M Thompson, David James McConkey, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2022)

4522 Background: Neoadjuvant cisplatin-based chemo followed by radical cystectomy (RC) is a standard of care treatment for pts with MIBC. DDR gene mts, including within ERCC2, a DNA helicase implicated in cisplatin sensitivity in MIBC, have been associated with higher pathologic (path) downstaging ( &lt; pT2) and complete response (pT0) at RC and improved overall survival (OS) in retrospective series. S1314 randomized pts to one of 2 chemo regimens (dose dense MVAC or Gem/Cis) followed by RC. We sought to correlate ERCC2 and other DDR gene mts with response and survival in MIBC pts enrolled onto this prospective trial. Methods: Tumor and matched germline DNA from evaluable pts enrolled onto S1314 underwent exon capture sequencing of 505 cancer-associated genes (MSK-IMPACT). Both deleterious (del) mts and any mts in 9 DDR genes (ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, ATM, ATR, RAD51C, FANCC) were correlated with clinical outcomes. The prespecified analyses included the association of mts with &lt; pT2 and pT0 by logistic regression analysis and with progression-free survival (PFS) and OS by Cox proportional hazards regression. Results: 179 patients (median 61 years, 85% male, 87% white, and 87% clinical stage T2) who received &gt;2 cycles of chemo and were evaluable for path response were included in the analysis. The pT0 rate was 28% and &lt; pT2 was 41%. Del mts in ERCC2 were detected in 26 (14%) pts followed by ATM (n = 12, 7%), ATR (n = 3) and BRCA2 (n = 2). ERCC2 mts were associated with statistically significantly higher path responses with a 54% pT0 rate and 62% downstaging rate. Patients with any del mts had higher path response rates (51% pT0, 56% &lt; pT2) and better PFS (Table) with a median follow-up of 53 months. There was a non-significant trend towards improved OS. Conclusions: In pts managed with neoadjuvant chemo and RC on S1314, both ERCC2 mts and del DDR gene mts correlated with pathologic response. Any del DDR gene mt was associated with improved PFS. These results are in line with retrospective analyses displaying a correlation between DDR gene mts and neoadjuvant chemosensitivity in MIBC and support ongoing genomically-informed organ sparing trials.[Table: see text]
Ground-glass opacity showed response to immunotherapy in cancer patients.
Authors: Fang Wu, Chunhong Hu, Xiaohan Liu, Yizheng Li, Yue Zeng, Liuer He, Junqi Liu
Journal: Journal of Clinical Oncology (2022)

e14605 Background: Ground glass opacities (GGO) are lesions with hazy density on CT. Immune checkpoint inhibitors (ICIs) achieved a significant improvement in the treatment of early and advanced non-small lung cancer (NSCLC). It is unclear whether ICI therapy show efficacy on GGO lesions. Methods: As the largest diameter of most lesions was less than 10mm, the definition of evaluable lesion we expanded the lower limit of the diameter to 4 mm. We retrospectively assessed cancer patients with GGOs who underwent at least two courses of immunotherapy between January 2016 and June 2021 in Second Xiangya hospital, China. Also, we evaluated GGOs that had been examined by low-dose thin-slice CT more than twice. Wilcoxon test was used to evaluate the length and diameter changes of GGO. We assessed the correlation between CT imaging features of GGO and the efficacy of immunotherapy through univariate and multivariate logistic regression. Results: Among eligible patients (n = 51), 35 were lung cancer patients and 16 were other tumor patients. Confirmed 95 GGOs were included. 68 GGOs were from lung cancer patients and 27 GGOs were from patients with other types of cancer (such as esophageal carcinoma, oral squamous cell carcinoma and hepatocarcinoma etc.). The diameter of GGO decreased significantly after immunotherapy (7.56 vs 4.31, P = 0.000). The same results were observed in lung cancer patients (7.98mm vs 4.92mm, P = 0.000) and in non-lung cancer patients (6.90mm vs 3.35mm, P = 0.001). The volume of GGO shirked significantly after immunotherapy in cancer patients (297.35mm 3 vs 125.46mm 3 , P = 0.000) lung cancer patients (401.41 mm 3 vs 164.91 mm 3 , P = 0.007) and non-lung cancer patients (137.93mm 3 vs 65.04mm 3 , P = 0.000). Conclusions: GGO can response to immunotherapy, which indicates immunotherapy maybe potentially helpful for patients with multiple GGO lesions such as multiple primary lung cancer (MPLC) patients.